Ethanol dependence is a widespread affliction with annual cost to society in the hundreds of billions of dollars. Drug dependence is generally regarded as the inability to abstain from drug use despite the known negative consequences and is often accompanied by symptoms of physical withdrawal during protracted periods of abstinence. Chronic drug abuse has been shown to induce neurobiological changes that are thought to underlie the progression to compulsive drug seeking behaviors. Current research in ethanol dependence largely focuses upon the mesolimbic dopamine system, of which, the nucleus accumbens (NAc) plays a central role in the processing of neural information related to rewarding stimuli. In order to effectively treat ethanol dependence, it is vital to determine which specific changes in neural circuit function contribute to the shift from a normal to an ethanol dependent state. One mechanism through which neurons can reorganize themselves in response to different stimuli is called synaptic plasticity. Plasticity mechanisms are thought to participate in the rewiring of neural circuits in response to drugs of abuse. Our understanding of the synaptic and intracellular processes controlling plasticity of the principle neurons, called medium spiny neurons (MSNs), of such an important brain structure is lacking. This proposal builds on preliminary studies that indicate MSNs from the NAc exhibit a reversal of synaptic plasticity following in vivo chronic intermittent ethanol exposure. This finding is significant because this switch in synaptic plasticity from depression to potentiation is a direct example of the rewiring of normal cellular activity thought to occur in the drug-dependent brain. The overarching hypothesis of this proposal is that neuroadaptive alterations in excitatory synaptic plasticity in the NAc contribute to the expression of ethanol dependence. The first part of this proposal is structured to elucidate the mechanisms underlying the conversion from synaptic depression to potentiation. MSNs are commonly separated into two subpopulations based on their expression of specific dopamine receptor subtypes, which project to different brain structures. The second half of this proposal will use transgenic mouse lines to investigate the propensity of these two subpopulations of MSNs to exhibit differing forms of synaptic plasticity before and after ethanol exposure. These experiments will be the first to investigate the ethanol modulation of synaptic plasticity in the NAc. The results should provide new insights that will help to identify novel sites for future development of pharmacologic agents for the treatment of alcoholism. PUBLIC HEALTH RELEVANCE: Alcoholism and complications from alcohol dependence make up the fourth leading cause of death in the U.S., and the resulting health care-related expenses are estimated at nearly $200 billion annually. This proposal contributes to ongoing research aimed at discovering what changes occur in the brain as a person becomes an alcoholic. Research in this area is vital to uncover new and effective treatments to help those affected with alcohol-use disorders recover and contribute positively to society.